This investigation represents a continuation of on-going research, under grant GM 19568, on the pharmacokinetics of salicylate (SA) in infants and children for the purpose of increasing the safety and efficacy of analgesic, antipyretic and antiinflammatory therapy. The proposed research also encompasses certain related problems such as the pharmacokinetics of a frequently used alternative to aspirin, i.e., acetaminophen. Detailed pharmacokinetic and biochemical studies are proposed to determine the mechanism(s) of the pronounced inter-individual differences in salicylate pharmacokinetics in children with connective tissue (inflammatory) disease and to develop a basis for rational, safe and effective salicylate therapy for such children. Other proposed studies are designed to explore the disposition of transplacentally acquired salicylate by newborn infants and animals, and the interaction of this drug with bilirubin. The mechanism of salicylate-induced hepatotoxicity will be studied on animal models and the pharmacokinetics of salicylate will be determined in selected patients with aspirin-induced elevation of transaminase in serum. The effect of plasma protein binding on the pharmacokinetics of salicylate will be investigated in laboratory animals and in man. The plasma protein binding of salicylate will be determined during pregnancy as a function of time, with plasma samples obtained from non-medicated volunteer subjects. In vitro and animal studies are proposed to develop means for preventing or minimizing acetaminophen-induced hepatotoxicity.